Annually, the US has 30,000+ suicides and ten times as many suicide attempts. Unfortunately, mortality and morbidity have remained steady over the last two decades, suggesting that a paradigm shift in prevention is required. Such a shift hinges on improving our knowledge regarding the causes of suicidal behavior. The Conte Center will employ a multidisciplinary approach to study how reported childhood adversity can mold the diathesis for suicidal behavior. Project 1 (Arango) will use postmortem brain tissue from suicides with major depressive disorder (MDD) to examine the relationship of childhood adversity (psychological autopsy) to candidate gene expression in neurons from prefrontal cortex, anterior cingulate cortex and hippocampus, as well as growth and apoptotic factors, HPA axis indices and targets in terms of neuron and glial number and the serotonin system. Correlations with suicide and aggressive traits will be determined. Project 2 (Champagne) will use a maternal deprivation mouse model to examine effects on DNA methylation and expression of the same genes, and effects on the same brain biology and depression, anxiety and aggressive behaviors. Project 3 (Mann) and Project 4 (Ochsner) will study the same set of MDD suicide attempters, MDD nonattempters and healthy volunteers and quantify brain neurotransmitter indices and fMR responses to evaluate cognitive control of emotion, each relevant to major depression and suicidal behavior. They will evaluate the relationship of identified circuitry changes to reported childhood adversity. Project 5 (Stanley) will clinically characterize all the subjects in P3 and P4 and then determine the relationship of reported childhood adversity to aggressive traits (reactive and proactive aggression) and then relate aggression type to stress responsiveness and type of suicidal behavior. Aggression and stress responses will be measured by lab tests and by ecological momentary assessment in the real world. Findings in P5 and P3 are compared in exploratory aims (impaired serotonin function and greater aggression) and P4 (reactive individuals and weaker cognitive control over mood). Project 6 (Ogden) will use high dimensional brain imaging data to develop a novel method to measure risk for suicidal behavior. This method can then be applied to genetic and other high dimensional data sets. These projects will help elucidate how early adverse experiences affect gene expression and brain biology to increase risk of suicidal behavior later in life.